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General Information

Spravato (esketamine) nasal spray is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist.

Spravato is specifically indicated for use, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults.

Spravato is specifically indicated to treat depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior.

Spravato is supplied as a spray for intranasal administration.

The recommended dosage for TRD is as follows:

Induction Phase Weeks 1 to 4: Administer twice per week; Day 1 starting dose: 56 mg followed by subsequent doses of 56 mg or 84 mg
Maintenance Phase Weeks 5 to 8: Administer once weekly at 56 mg or 84 mg. Week 9 and after: Administer every 2 weeks or once weekly at 56 mg or 84 mg. Dosing frequency should be individualized to the least frequent dosing to maintain remission/response.

The recommended dose for Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior is as follows:

Administer Spravato 84 mg twice per week for 4 weeks in conjunction with an oral antidepressant (AD). The Spravato dosage may be reduced to 56 mg twice per week based on tolerability. After 4 weeks of treatment with Spravato, evidence of therapeutic benefit should be evaluated to determine need for continued treatment. The use of Spravato, in conjunction with an oral antidepressant, beyond 4 weeks has not been systematically evaluated in the treatment of depressive symptoms in patients with MDD with acute suicidal ideation or behavior.

Clinical Results

FDA Approval

The FDA approval of Spravato for TRD was based on three short-term (four-week) clinical trials and one longer-term maintenance-of-effect trial. In the three short-term studies, patients were randomized to receive Spravato or a placebo nasal spray. All patients in these studies started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms. In one of the short-term studies, Spravato nasal spray demonstrated statistically significant effect compared to placebo on the severity of depression, and some effect was seen within two days. The two other short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with Spravato plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.

The FDA approval of Spravato for the treatment of depressive symptoms in patients with MDD with acute suicidal ideation or behavior was based on two identical randomized, double-blind, multicenter, placebo-controlled phase 3 studies. In these studies, patients received treatment with Spravato 84 mg or placebo nasal spray twice-weekly for 4 weeks. After the first dose, a one-time dose reduction to Spravato 56 mg was allowed for patients unable to tolerate the 84 mg dose. All patients received comprehensive standard of care treatment, including an initial inpatient psychiatric hospitalization and a newly initiated or optimized oral antidepressant (AD) (AD monotherapy or AD plus augmentation therapy) as determined by the investigator. Spravato plus comprehensive standard of care demonstrated a significant, rapid reduction of depressive symptoms within 24 hours, with some patients starting to respond as early as four hours. Spravato plus comprehensive standard of care led to a 15.9 and 16.0 point decrease on the Montgomery-Åsberg Depression Rating Scale (MADRS) in the two trials at 24 hours after the first dose of study medication. This compared to a reduction of 12.0 and 12.2 points in the placebo plus comprehensive standard of care group. Both the Spravato and placebo groups continued to improve between four hours and 25 days, with 41 percent and 43 percent of the Spravato plus comprehensive standard of care group achieving clinical remission of depression (minimal or no symptoms) compared with 34 percent and 27 percent in the placebo groups, by the end of the double-blind period, in the two trials, respectively.

Side Effects

Adverse effects associated with the use of Spravato may include, but are not limited to, the following:

dissociation

dizziness

nausea

sedation

vertigo

hypoesthesia

anxiety

lethargy

blood pressure increased

vomiting

feeling drunk

The Spravato drug label comes with the following Black Box Warning: Risk for sedation and dissociation after administration. Monitor patients for at least two hours after administration. ● Potential for abuse and misuse. Consider the risks and benefits of prescribing Spravato prior to using in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse. ● Spravato is only available through a restricted program called the Spravato REMS. ● Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Spravato is not approved for use in pediatric patients.

Mechanism of Action

Spravato (esketamine), the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity.